The Antidepressant-like Activity and Cognitive Enhancing Effects of the Combined Administration of (R)-Ketamine and LY341495 in the CUMS Model of Depression in Mice Are Related to the Modulation of Excitatory Synaptic Transmission and LTP in the PFC
Pharmaceuticals February 1, 2023 A. Pałucha-poniewiera, B. Bobula, A. Rafało-ulińska
A combination of (R)-ketamine and an mGlu2/3 receptor antagonist (LY341495), called mixRL, produced rapid and sustained antidepressant effects in mice subjected to chronic unpredictable mild stress (CUMS), a model of depression. A single dose reversed CUMS-induced memory deficits and depression-like behaviors. Electrophysiological recordings showed that mixRL normalized increased field potential amplitudes and paired-pulse responses in the prefrontal cortex (PFC) of stressed mice and restored reduced long-term potentiation (LTP). The findings suggest that mixRL's antidepressant and cognitive-enhancing actions involve modulation of glutamatergic transmission and synaptic plasticity in the PFC, with a low risk of side effects.